Abstract (of the Parent Award) Anxiety and related disorders, including obsessive-compulsive disorder (OCD), are leading causes of global disability. Brain circuit abnormalities have been identified, but important knowledge gaps remain. It is unclear which abnormalities underlie what symptom profiles, how dysfunction develops and thus which brain abnormalities to target with new interventions. Moreover, circuit abnormalities likely cut across traditional diagnostic categories and, within a diagnostic category, there is individual variability. Our approach is to identify reproducible brain signatures of measurable behaviors and clinical symptoms; these brain signatures can then be used to reveal trans-diagnostic disease dimensions, to chart their development, and to develop treatments that target these circuit abnormalities directly. The goal of this proposal is to identify reproducible brain signatures associated with cognitive and clinical profiles that are common in individuals with OCD. To accomplish this, we will study 250 unmedicated OCD and 250 healthy control subjects (HCs) at five expert research sites spanning five countries (U.S., Brazil, India, Netherlands, and South Africa). Using imaging methods that could ultimately be adapted for clinical use, we will examine multiple brain circuits thought to underlie OCD behaviors, focusing on morphometry (using T1- weighted MRI), structural connectivity (using Diffusion Tensor Imaging [DTI]), and functional connectivity (using resting-state fMRI [rs-fMRI]). We will identify neuroimaging signatures that distinguish individuals with OCD from HCs by analyzing each modality with standardized protocols and by using multi-modal fusion with modern machine learning statistical methods. We will then examine how these imaging signatures are linked to behavioral performance on cognitive tasks that probe these same circuits and to a range of clinical profiles that are common to OCD. Finally, we will explore how specific environmental features (childhood trauma, socioeconomic status, religiosity) may moderate this brain-behavior relationship. Our short-term goal is to identify brain signatures of OCD cognitive and clinical profiles, leveraging our global collaboration both to recruit a very large unmedicated sample and to prove these signatures' reproducibility. Our long-term goal is to identify brain signatures for measurable behaviors and clinical symptoms that cut across traditional diagnostic categories and to use these signatures to transform how we conceptualize, diagnose and ultimately treat mental illnesses like OCD.